Cell signaling pathways regulate cell growth, proliferation, and apoptosis. Kinases transduct signals for cell growth or apoptosis by phosphorylation of their substrates, which are mostly downstream kinases involved in cell signaling processes themselves. The activity of kinases is regulated by phosphorylation and dephosphorylation effecting conformational changes in the kinases. Overexpression or constitutive activation of kinases involved in anti-apoptotic or proliferation signaling pathways are one typical feature of tumor cells (Cross, T. G., et al., Exp. Cell Res. 256 (2000) 34-41).
The family of serine/threonine kinases (AKT) proteins are located downstream in the PI-3 kinase pathway and phosphorylate a burgeoning list of substrates involved in several pathways for cell survival and inhibition of apoptosis as has been shown recently (Kandel, E. S., and Hay, N., Exp. Cell Res. 253 (1999) 210-229; Blume-Jensen, P., and Hunter, T., Nature 411 (2001) 355-365; Datta, S. R., et al., Genes Dev. 13 (1999) 2905-2927). Constitutive activation of AKT1 is frequently found in human prostate, breast, and ovarian carcinomas. It is due to a complete loss of lipid phosphatase PTEN gene, a negative regulator of the PI-3 kinase pathway (Nesterov, A., et al., J. Biol. Chem. 276 (2001) 10767-10774). These data indicate that AKT1 kinase is a central player in tumorigenesis and a potential target for cancer intervention. Inhibitors of AKT1 kinase are promising reagents for cancer therapy as effective sensitizers or inducers of apoptosis (Beresford, S. A., et al., J. Interferon Cytokine Res. 21 (2001) 313-322).
AKT1 belongs to the family of protein kinases. It exhibits a sequence homology to PKC and PKA. Several structural classes of PKC and PKA inhibitors are known. More specifically, WO 94/20062 (by Sphinx Pharmaceuticals Corporation, “Balanoids”), WO 95/30640 (by Eli Lilly and company, “Substituted fused and bridged bicyclic compounds as therapeutic agents”), WO 97/02249 (by F. Hoffmann-La Roche, “Novel azepanes and their ring homologues for therapy and prophylaxis of protein kinase mediated diseases”), and EP 0 663 393-A1 (by F. Hoffmann-La Roche, “Neue 3-Amino/Hydroxy-4-[4-Benzoyl-Phenyl Carbonylamino/oxy]-Azepane und Homologe als Protein Kinase Hemmer”) disclose balanol derivatives with PKC inhibitory activity. Bisindolylmaleimides are reported as PKC inhibitors in EP 0 657 458-A1 (by Eli Lilly, “Protein kinase C inhibitors”), EP 1 020 471-A1 (by Kyowa Hakko Kogyo Co., “Process for producing UCN-01”), and EP 0 296 110-A2 (by Ciba-Geigy AG, “An Methylamino-Stickstoff substituierte Derivate von Staurosporin”). No AKT1 small molecule inhibitors are disclosed in the literature.
It has now been found that certain novel azepane derivatives are potent inhibitors of AKT1 in vitro and in various tumor cell lines, possess anti-cell-proliferation properties, induce apoptosis and are plasma stable which makes them more potent than those in the aforementioned references.